The development and activation of cells of various types is largely controlled by signals generated by Src-family protein tyrosine kinases (SFKs). We have been involved in studies of the physiological significance of SFKs in lymphocytes by generating mice with conditional inactivation of the major SFK inhibitory kinase, Csk, and showing the essential role of Csk in antigen dependent development of T cells. We have also identified a novel transmembrane Csk binding phosphoprotein (Cbp), which plays a key role in Csk-mediated inhibition of SFKs. While working on the role of SFKs in immunity, we recognized the fundamental lack of information about the expression and role of SFKs in DCs. Here we propose experiments which will reveal the complexity of the SFK network in DCs and will show the role of SFKs and their negative regulators, Csk and Cbp, in differentiation and function of DCs of various lineages. We will use SFK mutant mice and DCs with conditional inactivation of the csk or cbp genes to address an impact of SFK modification on DC function in vivo. We have also found a potent regulator of B cell activation, Toll-like receptor protein RP105, being expressed on DCs. In the current application, we describe experiments that will address the role and mechanisms of RP105-mediated DC activation. In some of these experiments, we will employ RP105-deficient mice that we generated. Collectively, the proposed experiments will enrich our knowledge about the role of SFKs in signaling mechanisms controlling DC differentiation, survival and activation.